tbuckley/cabot-search huggingface dataset:
Abstract SY23-03: Mesenchymal lineage heterogeneity as a determinant of matrix composition and tumor progression
Authors: Mara H. Sherman
Journal: Cancer Research (2022)

Abstract The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have developed a novel mouse model to track PSC differentiation and function during pancreatic tumor progression in vivo. This model revealed that PSC-derived CAFs in fact give rise to a numerically minor but functionally significant subset of PDAC CAFs, and may represent a viable therapeutic target. We adapted our mouse model to enable targeted ablation of PSCs and derivative CAFs within their host tissue for the first time. Functional studies in this model reveal non-redundant functions for PSC-derived CAFs in shaping the PDAC microenvironment, and highlight the significance of mesenchymal lineage heterogeneity for pancreatic tumorigenesis. Further, we find that tumor genotype with respect to p53 status dictates stromal evolutionary routes with respect to cell of origin, a finding that may extend to additional cancer cell-intrinsic genomic alterations. Together, these findings shed light on mechanisms that shape the tumor microenvironment during pancreatic cancer progression, and may hold relevance in additional solid tumor types. Citation Format: Mara H. Sherman. Mesenchymal lineage heterogeneity as a determinant of matrix composition and tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-03.
Abstract 5910: Exploration of genetic ancestry and socioeconomic status in the incidence of neuroblastoma: An ecological study
Authors: Eun Mi Jung, Rebecca A. Johnson, Aubrey Hubbard, Logan G. Spector
Journal: Cancer Research (2022)

Abstract Although global differences in the incidence of neuroblastoma have been examined, the underlying mechanism has yet to be elucidated. Previous studies have suggested genetic ancestry and human development index (HDI) as contributing factors, but few studies have been conducted at the international level. Here, we aimed to examine whether the frequency of common genomic variation associated with neuroblastoma can affect its risk at the ecological level with consideration of the socioeconomic status of a population. Minor allele frequencies (MAFs) for 22 single nucleotide polymorphisms (SNPs) were abstracted from the Geography of Genetic Variants Browser. The number of incident neuroblastomas for each population was obtained from the Cancer Incidence in Five Continents series. Further, population pseudo-polygenic risk scores (pp-PRSs) were calculated as a sum of MAFs at the population level, each of which was weighted by effect sizes from prior studies. Negative binomial regression was used to estimate the incidence rate ratios (IRRs) and the 95% confidence intervals (CIs) to examine whether differences in MAFs across the population influence the risk of neuroblastoma, with and without adjustment for HDI and whether pp-PRSs can be a predictor of the risk of neuroblastoma. Overall, our results indicated that the neuroblastoma risk associated with variation in SNP frequency could not be differentiated from that of HDI at the ecological level. Additionally, pp-PRSs were not significantly associated with the risk of neuroblastoma (IRR: 0.99, 95% CI: 0.62—1.60). Further study using individual-level data is warranted to minimize the ecological fallacy in this study. Citation Format: Eun Mi Jung, Rebecca A. Johnson, Aubrey Hubbard, Logan G. Spector. Exploration of genetic ancestry and socioeconomic status in the incidence of neuroblastoma: An ecological study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5910.
Abstract 5014: The landscape of ERBB2 mutations in Chinese patients with solid tumors
Authors: Xiangyu Su, Hongmei Zhao
Journal: Cancer Research (2022)

Abstract Background: Receptor tyrosine kinase (ERBB2) is altered by mutations and amplifications in various cancer types. Meanwhile, FDA approved some drugs to use for variants in ERBB2. However, the landscape of ERBB2 mutations and copy number variants (CNV) in pan-cancer is unknown in Chinese. Methods: 599 gene-panel by next-generation sequencing (NGS) was performed on 2,570 patients with solid tumors including non-small cell lung cancer (NSCLC) (n = 660), esophagogastric (n = 89), colorectal (n = 966), breast (n = 156) and gastric cancer (n = 699). The mutations and CNV in ERBB2 were detected for characterize the landscape in Chinese patients with solid tumors. Results: The frequency of single nucleotide variants (SNV) and CNV in ERBB2 was 9% and 4.3% in pan-cancer and the rate of variants was 13.3%. The most frequency of CNV was occurred in breast cancer and the last was in non-small cell lung cancer (13.5% vs 1.1%). Nevertheless, the rate of SNV in different cancer species was almost the same as in pan-cancer (mean: 8.8%). The higher rate of variants in ERBB2 was breast cancer and the lower was NSCLC. The cancer types with the highest incidence of ERBB2 variants were the following: breast (22.4%), gastric adenocarcinoma (18.3%), esophagogastric cancer (11.2%), colorectal cancer (10.8%) and NSCLC (9.7%). Conclusion: Based on the results, the profile of variants in ERBB2 revealed more patients may profit from FDA-approval drugs in China. The patients with somatic mutations in ERBB2 are treated with trastuzumab deruxtecan and adotrastuzumab emtansine in NSCLC. The patients with amplification are treated with trastuzumab deruxtecan in most tumors, but margetuximab and chemotherapy can cure breast cancer, according to FDA-approval. Keywords: ERBB2 mutations, CNV, SNV, solid tumors Citation Format: Xiangyu Su, Hongmei Zhao. The landscape of ERBB2 mutations in Chinese patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5014.
Abstract 2364: ABI1 regulates transcriptional activity of STAT3
Authors: Xiang Li, Baylee Porter, Allysa Kemraj, Alaji Bah, Marcin Kortylewski, Leszek Kotula
Journal: Cancer Research (2022)

Abstract Background: Prostate cancer (PCa) is characterized by the complexity of oncogenic signaling and heterogeneity of transcriptional landscapes. Adaptor protein ABI1 is a tumor suppressor in PCa as evidenced by its loss or downregulation in high grade and metastatic tumors. STAT3 activation is a hallmark of high-risk prostate tumors. ABI1 loss is associated with STAT3 activation leading to transcriptional reprogramming and epithelial-mesenchymal-transition (EMT) of prostate cancer cells (Nath, Li et al. 2019 Cell Commun Signal). EMT changes involve several homeobox transcription factors. The fact that ABI1 contains a homeobox homology region (HHR) suggested the possibility that it plays a role in EMT through directly regulating transcriptional activity by DNA binding. Methods: To examine this hypothesis we set out to analyze ABI1-DNA binding. We purified ABI1 HHR and demonstrated its in vitro interactions with different homeobox DNA-binding consensus of double-stranded DNA sequences. We created DU145 ABI1 CRISPR KO cell line and rescue ABI1 expression using retroviral transfection with either ABI1 wild type or Abi1 HHR mutants. DU145 cell lines STAT3 cellular localization was studied by Immunofluorescence staining and the STAT3 transcription activities was studied by Firefly Luciferase Assays with STAT3 specific luciferase reporter plasmid. Results: We found that the presence of alternatively spliced Exon 4-encoded sequence, located in the C-terminus of HHR, regulates binding of ABI1 to DNA. Structural NMR studies confirmed ABI1 binding to DNA. Subsequent functional studies using DU145 CRISPR KO cell lines expressing wild type or HHR mutants of ABI1 demonstrated that HHR regulates the nuclear localization and transcriptional activity of STAT3. Conclusion: We propose that ABI1 is a critical regulator of STAT3 activity during prostate cancer progression by the ABI1 HHR mediated DNA binding mechanism. Funding resources: NCI R01 CA161018; R21 CA260381 Conflicts of Interest Disclosure Statement: The authors declare no conflicts of interest. Citation Format: Xiang Li, Baylee Porter, Allysa Kemraj, Alaji Bah, Marcin Kortylewski, Leszek Kotula. ABI1 regulates transcriptional activity of STAT3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2364.
Normalising menopause
Authors: Martha Hickey, Myra S Hunter, Nanette Santoro, Jane Ussher
Journal: BMJ (2022)

Three patients are reported on who presented with communicating hydrocephalus due to presumed tuberculous meningitis. Subsequent clinical deterioration despite antituberculous chemotherapy prompted reassessment with FDG-PET scanning and meningeal biopsy in one case and repeat CSF cytology with special staining in the second. The third patient died and postmortem confirmed a diagnosis of primary diffuse leptomeningeal gliomatosis. In the first two patients, MRI of the entire neuraxis showed no evidence of a primary intraparenchymal tumour. These cases emphasise the need for repeated reassessment in patients with culture negative lymphocytic meningitis. In addition, this is the first report of FDG-PET scanning in leptomeningeal gliomatosis.
Abstract 3066: Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations
Authors: Alexa Morales Arana, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, Luis G. Carvajal-Carmona
Journal: Cancer Research (2022)

Abstract Gastric cancer (GC) is the 5th most common neoplasm and the 2nd most deadly cancer worldwide, with an estimated 783,000 deaths in 2018. Furthermore, Hispanic/Latino Americans continue to be underrepresented in GC genomic studies despite being twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites (NHW). In order to address this pervasive health disparity, our lab has led efforts to characterize tumor biopsies from racial/ethnic minority cancer patients to inform more effective cancer treatment and advance precision medicine among these high-risk populations. We performed whole-exome sequencing of 31 GC patient tumors with more than 60% of the samples coming from minority patients. We identified higher somatic mutation frequencies in the ARID1A, BRCA2, and APC genes compared with the TCGA GC cohort, which is made up of mostly NHW patients. To better understand the role these genes play in cancer tumorigenesis among racial/ethnic minority GC patients, our lab has established a CRISPR/Cas9 genome-editing platform in minority patient-derived organoids (mPDOs). In this study, we utilized our platform to generate mPDO models of APC-TP53 double knockouts (dKO), ARID1A-TP53 dKO, and TP53-ARID1A-BRCA2 triple knockouts in organoid lines derived from normal gastric tissue. We developed medium to select for functional mutants following organoid cell electroporation that yielded near-complete selection for the desired gene knockouts, allowing us to generate isogenic mPDO lines modeling each gene KO combination. Our organoid models will provide a critical method to elucidate therapeutic sensitivity and resistance mechanisms in minority groups towards the ultimate goal of addressing GC health disparities in US racial/ethnic minorities. Citation Format: Alexa Morales Arana, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, University of California Minority Patient-DerivedXenograft (PDX) Development and Trial (UCaMP) Cent, Luis G. Carvajal-Carmona. Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3066.
Abstract LB225: Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping
Authors: Jarrett D. Egertson, Cassandra Stawicki, Taryn E. Gillies, James H. Joly, Noah Steiner, Kevin Cardenas, Jonathan B. Leano, Kevin Chen, Sophie Watts, Hunter B. Boyce, Dan DiPasquo, Alana Killeen, Vadim Lobanov, Greg Kapp, Sujal Patel, Parag Mallick
Journal: Cancer Research (2022)

Abstract Protein Identification by Short-epitope Mapping (PrISM) is a novel proteomics method with the goal of comprehensive proteome quantification at single-molecule sensitivity. In this work, we present computational modeling demonstrating the feasibility of this goal and experimental application of the approach leveraging single-molecule protein measurements to identify a small number of model proteins. The implementation of PrISM as presented works by acquiring sequential affinity reagent binding measurements on single protein molecules. Counterintuitively, using affinity reagents with “poor” specificity (i.e. cross-reacting to many proteins) enables identification of tens of thousands of proteins with only hundreds of affinity reagents. To experimentally demonstrate PrISM, we use a small number of affinity reagents to quantify a larger number of proteins. In simulations, PrISM is able to identify more than 98% of proteins in human, mouse, yeast, and E. coli using 300 affinity reagents targeting short trimer epitopes. PrISM is robust to experimental confounders including non-specific binding and noisy, incomplete, or inaccurate estimation of affinity reagent to protein binding characteristics. Simulations of the approach with a chip containing 10 billion protein molecules measured in parallel show a dynamic range of detection of up to 9.5 and 11.5 orders of magnitude for HeLa cells and plasma, respectively. Using such a chip, the PrISM method can identify and quantify over 90% of the human proteome in a single experiment, potentially revolutionizing biomarker discovery and cancer research. Citation Format: Jarrett D. Egertson, Cassandra Stawicki, Taryn E. Gillies, James H. Joly, Noah Steiner, Kevin Cardenas, Jonathan B. Leano, Kevin Chen, Sophie Watts, Hunter B. Boyce, Dan DiPasquo, Alana Killeen, Vadim Lobanov, Greg Kapp, Sujal Patel, Parag Mallick. Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB225.
Abstract 6142: Gain-of-function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy
Authors: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi
Journal: Cancer Research (2022)

Abstract The immune microenvironment plays a critical role in cancer development, progression and resistance to therapy. Specific tumor genotypes can profoundly influence the composition of the immune microenvironment. After oncogenic KRAS, TP53 is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC). KRASG12D mutations in tumor cells are known to modify the immune landscape of PDAC, however the immune effects of neomorphic TP53 mutations have not been defined. Focusing on the most common neomorphic TP53 mutation in human PDAC, we sought to evaluate the non-cell-autonomous role of gain-of-function mutant Trp53R172H in modulating the immune microenvironment of pancreatic tumors by using KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) genetically engineered to express the Trp53R172H gain-of-function. Orthotopically implanted tumors derived from CRISPR-generated KrasG12D/+;Trp53R172H/+ PDEC had a distinct immune profile in comparison to KrasG12D/+;Trp53+/+ tumors, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link gain-of-function mutant Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy. Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Gain-of-function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6142.
Immune response to vaccination against SARS-CoV-2 in hematopoietic stem cell transplantation and CAR T-cell therapy recipients
Authors: Xi Wu, Lu Wang, Lu Shen, Lin He, Kefu Tang
Journal: Journal of Hematology & Oncology (2022)

Abstract Recipients after hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at increased risk for unfavorable outcomes after SARS-CoV-2 infection. The efficacy of COVID-19 vaccines remains undetermined in this vulnerable population, we therefore conducted a pooled analysis to evaluate the immune response after vaccination. A total of 46 studies were finally included, comprising 4757 HSCT and 174 CAR-T recipients. Our results indicated that HSCT and CAR-T recipients had an attenuated immune response to SARS-CoV-2 vaccination compared with healthy individuals, while time interval between transplant and vaccination, immunosuppressive therapy (IST) and lymphocyte counts at vaccination significantly affected the humoral response in HSCT recipients. In addition, seroconversion was significantly higher in patients with BCMA-based CAR-T than those with CD19-based CAR-T. Thus, an adapted vaccination strategy for HSCT and CAR-T recipients may be required, and further research on the effect of a booster dose of COVID-19 vaccine and the role of cellular response after vaccination is warranted.
Abstract 843: Isoform-specific disruption of the <i>TP73</i> gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin
Authors: Xiangmudong Kong, Wenqiang Sun, Jin Zhang, xinbin Chen
Journal: Cancer Research (2022)

Abstract TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α-η). Interestingly, TAp73 is shown to have opposing functions in tumorigenesis but the mechanism remains unclear. Here, we showed that deletion of exon 11 (E11) switches p73α to p73γ, the latter of which has oncogenic activities. Moreover, E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, chronic inflammation and tumor incidence, indicating that p73γ cannot compensate p73α for tumor suppression and fertility. E11-deficient mice were also prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine, was highly induced by p73γ and necessary for p73γ-mediated oncogenic activity. Importantly, p73α-γ isoform switch was detected in dog lymphomas and human prostate carcinomas along with elevated expression of Leptin. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism. Citation Format: Xiangmudong Kong, Wenqiang Sun, Jin Zhang, xinbin Chen. Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 843.
Abstract 5115: Combine high risk factors with circulating tumor DNA (ctDNA) to assist adjuvant chemotherapy (ACT) decision in Stage II colorectal cancer (CRC)
Authors: Xie Gui Yuan, Liu Miao, Huang Meng Li
Journal: Cancer Research (2022)

Abstract Background: Approximately 10% to 15% have residual disease after surgery in patients with stage II CRC. Identification of this high-risk population and treatment with ACT could potentially reduce their risk of recurrence. However, the relative contribution of the factors used to define high risk stage II disease needs better understanding, although post-surgical ctDNA has been studied as a marker for an elevated risk of recurrence in stage I-III colorectal cancer. Methods: Individual data from 3 early colorectal cancer clinical studies(Tie, 2016;Reinert, 2019; Chen, 2021) that included information on high-risk factors and post-surgical ctDNA status were collected and reanalysed for 595 patients with or without ACT. Results: In stage II CRC patients with ctDNA-negative not treated with ACT form the Tie cohort, with high-risk status (n=42) showed a significantly reduced recurrence-free survival (RFS) compared to those with low-risk status(n=122) [HR, 3.283; 95%CI, 1.398 to 14.18; P = 0.0116], but in the ctDNA-negative patients with high-risk status, ACT (n=32) or not did not affect the RFS(P=0.1758). It meant false negatives of ctDNA made for bias of survival analysis results. Interestingly, in other two cohorts of stage II CRC patients with ctDNA-negative not treated with ACT, high-risk status showed no difference in RFS compared to low-risk status (p=0.3429 and 0.3173, respectively). In addition to the low sample size, the contribution of defined high-risk factors in prognosis was worth exploring which meant pseudo high-risk status also affect survival analysis results. And there were big differences in the high-risk factors included in the three cohorts especially in ctDNA-negative patients, such as the proportion of lymph nodes (LN) yield &amp;lt;12 seemed higher in Tie cohort. Conclutions: It was not enough to predict recurrence depend on ctDNA status alone for stage II CRC. Different risk factors might have different prognostic weights so that different combinations of post-surgical ctDNA status and risk factors might be used to make more accurate ACT decision. Citation Format: Xie Gui Yuan, Liu Miao, Huang Meng Li. Combine high risk factors with circulating tumor DNA (ctDNA) to assist adjuvant chemotherapy (ACT) decision in Stage II colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5115.